A New Route to Pain Treatment

So often, nature holds the key to medical advancement. This is the hope that drives the scientists studying marijuana to better understand the brain’s mechanisms for coping with pain.

What they know is that marijuana’s efficacy as a pain-killer comes from its activation of a set of proteins known as cannabinoid receptors, which also regulate appetite, inflammation, and memory.

With the goal of understanding and ultimately producing treatments that capitalize on marijuana’s beneficial effects, researchers have focused their attention on the components of the cannabinoid system that the human body naturally activates. These include N-arachidonoyl ethanolamine (AEA) and 2-arachidonoylglycerol (2-AG).

In order to understand the role that each of these components plays in the system, researchers need a way of regulating them individually in experimentation. To accomplish this, they have focused on the specific enzymes that break down AEA and 2-AG – fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) respectively. With chemicals capable of inhibiting these enzymes, scientists would have the tools that they need to manipulate AEA and 2-AG in order to pinpoint the exact role that they play in the cannibinoid system.

But this is where researchers hit a wall. Although there are a number of compounds being studied for their ability to break down FAAH, scientists could not find a compound that was effective in inhibiting MAGL.

“Tools as selective and efficacious as MAGL inhibitors just weren’t there,” explains Jonathan Long, a graduate student at the Scripps Research Kellogg School of Science and Technology who is a member of the Cravatt lab and a first author of a new paper on the topic.

To solve this problem, Long worked with the Cravatt team to develop about 200 compounds and test them using a chemical technique that they developed called Activity-Based Protein Profiling. Finally, the team struck gold: they found a chemical that is highly effective in blocking MAGL and called it JZL184 (named after Long’s initials and the order in the series of potential inhibitors tested).

JZL184 is exactly what researchers had needed – not only an effective block of MAGL, but a precise enough tool that it will not affect the more than 40 other related brain enzymes – to open the door for the first definitive study of 2-AG’s activity.

Employing their new tool, the researchers then found that the inhibition of MAGL and the resultant increase in 2-AG concentration indeed did reduce pain in mice. Furthermore, the 2-AG increase produced other effects associated with cannabinoid receptors such as hypothermia and decreased movement.

“This really does suggest a sort of segregation of labor, if you will,” explains Professor Benjamin Cravatt, the lab’s principal investigator and chair of the Department of Chemical Physiology, as he described the effects of elevated 2-AG versus AEA as part of the overall function of the cannabinoid system. “That, I think, is a truly unique result.”

Treatments based on inhibiting the other cannabinoid enzyme – FAAH – have already shown great promise for controlling pain. Now, with the tools to manipulate MAGL levels, Cravatt and Long are optimistic about the potential to advance treatments even further.

“There are so many different types of pain that it’s possible some types could be more effectively treated with one treatment than another,” Cravatt says.